European Biophysics Journal

, Volume 42, Issue 1, pp 61–70 | Cite as

Cardiac magnetic resonance imaging of rapid VCAM-1 up-regulation in myocardial ischemia–reperfusion injury

  • Stuart M. Grieve
  • Jacob Lønborg
  • Jawad Mazhar
  • Timothy C. Tan
  • Edwin Ho
  • Chia-Chi Liu
  • William Lay
  • Anthony J. Gill
  • Philip Kuchel
  • Ravinay Bhindi
  • Gemma A. Figtree
Original Paper

Abstract

Inflammatory response plays an important role in myocardial ischaemia–reperfusion (IR) injury. Up-regulation of vascular cell adhesion molecule-1 (VCAM) contributes to this. We examined the feasibility of using intravenously administered VCAM–MPIO (microparticle iron oxide) to characterize VCAM expression patterns in myocardial IR injury. Myocardial ischemia was simulated by 30 min of transient ligation of the left coronary vessel in rats. Purified, monoclonal, rat-specific, mouse VCAM antibody coupled to MPIO was administered through the tail vein at 3 h post reperfusion and the rats were sacrificed 1 h later. High resolution 3D ex vivo MRI images were acquired at 9.4 Tesla. Extensive foci of signal voids were observed on T2*-weighted gradient-echo sequences, which corresponded to focal deposits of MPIOs observed in histological sections. The spatial density of the signal voids (expressed as a percentage of pixels below a threshold value) was increased in the peri-infarct zone compared with non-infarct zone (32.5 ± 4 % vs. 13.9 ± 5 %; n = 6; p < 0.05) and was substantially greater than the signal loss due to non-specific binding seen in rats administered IgG control MPIO (2.0 ± 1 %; n = 6; p < 0.05). The VCAM-specific MPIO signal was also seen in myocardium and pericardium in segments remote from the IR injury, but not in rats undergoing a sham operation. In conclusion, molecular imaging in a model of myocardial IR injury is possible using high field MRI and VCAM–MPIOs and may provide novel insights beyond those achieved by standard histological and molecular analysis.

Keywords

Magnetic resonance imaging Myocardial ischemia–reperfusion VCAM-1 Inflammation Ventricular remodelling Molecular imaging 

References

  1. Akhtar AM, Schneider JE, Chapman SJ, Jefferson A, Digby JE, Mankia K, Chen Y, McAteer MA, Wood KJ, Choudhury RP (2010) In vivo quantification of VCAM-1 expression in renal ischemia reperfusion injury using non-invasive magnetic resonance molecular imaging. PLoS ONE 5:e12800PubMedCrossRefGoogle Scholar
  2. Ambrosio G, Tritto I (1999) Reperfusion injury: experimental evidence and clinical implications. Am Heart J 138:S69–S75PubMedCrossRefGoogle Scholar
  3. Bhindi R, Khachigian LM, Lowe HC (2006) DNAzymes targeting the transcription factor Egr-1 reduce myocardial infarct size following ischemia-reperfusion in rats. J Thromb Haemost 4:1479–1483PubMedCrossRefGoogle Scholar
  4. Bowden RA, Ding ZM, Donnachie EM, Petersen TK, Michael LH, Ballantyne CM, Burns AR (2002) Role of alpha4 integrin and VCAM-1 in CD18-independent neutrophil migration across mouse cardiac endothelium. Circ Res 90:562–569PubMedCrossRefGoogle Scholar
  5. Carlos TM, Schwartz BR, Kovach NL, Yee E, Rosa M, Osborn L, Chi-Rosso G, Newman B, Lobb R et al (1990) Vascular cell adhesion molecule-1 mediates lymphocyte adherence to cytokine-activated cultured human endothelial cells. Blood 76:965–970PubMedGoogle Scholar
  6. Chan W, Duffy S, Ellims A, Dart A, Taylor A (2011) Evidence for an acute diffuse fibrotic response throughout the left ventricle following acute myocardial infarction. Heart Lung Circ 20:S1–S155Google Scholar
  7. Chen IY, Wu JC (2011) Cardiovascular molecular imaging: focus on clinical translation. Circulation 123:425–443PubMedCrossRefGoogle Scholar
  8. Chen HH, Le Visage C, Qiu B, Du X, Ouwerkerk R, Leong KW, Yang X (2005) MR imaging of biodegradable polymeric microparticles: a potential method of monitoring local drug delivery. Magn Reson Med 53:614–620PubMedCrossRefGoogle Scholar
  9. Choudhury RP, Fisher EA (2009) Molecular imaging in atherosclerosis, thrombosis, and vascular inflammation. Arterioscler Thromb Vasc Biol 29:983–991PubMedCrossRefGoogle Scholar
  10. Entman ML, Smith CW (1994) Postreperfusion inflammation: a model for reaction to injury in cardiovascular disease. Cardiovasc Res 28:1301–1311PubMedCrossRefGoogle Scholar
  11. Gabrielsen A, Lawler PR, Yongzhong W, Steinbruchel D, Blagoja D, Paulsson-Berne G, Kastrup J, Hansson GK (2007) Gene expression signals involved in ischemic injury, extracellular matrix composition and fibrosis defined by global mRNA profiling of the human left ventricular myocardium. J Mol Cell Cardiol 42:870–883PubMedCrossRefGoogle Scholar
  12. Goldberg RJ, Currie K, White K, Brieger D, Steg PG, Goodman SG, Dabbous O, Fox KA, Gore JM (2004) Six-month outcomes in a multinational registry of patients hospitalized with an acute coronary syndrome [the global registry of acute coronary events (GRACE)]. Am J Cardiol 93:288–293PubMedCrossRefGoogle Scholar
  13. Hamoudeh M, Fessi H (2006) Preparation, characterization and surface study of poly-epsilon caprolactone magnetic microparticles. J Colloid Interface Sci 300:584–590PubMedCrossRefGoogle Scholar
  14. Hayward R, Campbell B, Shin YK, Scalia R, Lefer AM (1999) Recombinant soluble P-selectin glycoprotein ligand-1 protects against myocardial ischemic reperfusion injury in cats. Cardiovasc Res 41:65–76PubMedCrossRefGoogle Scholar
  15. Hemmingsson A, Carlsten J, Ericsson A, Klaveness J, Sperber GO, Thuomas KA (1987) Relaxation enhancement of the dog liver and spleen by biodegradable superparamagnetic particles in proton magnetic resonance imaging. Acta Radiol 28:703–705PubMedCrossRefGoogle Scholar
  16. Hoyte LC, Brooks KJ, Nagel S, Akhtar A, Chen R, Mardiguian S, McAteer MA, Anthony DC, Choudhury RP, Buchan AM, Sibson NR (2010) Molecular magnetic resonance imaging of acute vascular cell adhesion molecule-1 expression in a mouse model of cerebral ischemia. J Cereb Blood Flow Metab 30:1178–1187PubMedCrossRefGoogle Scholar
  17. Hwang WY, Foote J (2005) Immunogenicity of engineered antibodies. Methods 36:3–10PubMedCrossRefGoogle Scholar
  18. Jolly SR, Kane WJ, Hook BG, Abrams GD, Kunkel SL, Lucchesi BR (1986) Reduction of myocardial infarct size by neutrophil depletion: effect of duration of occlusion. Am Heart J 112:682–690PubMedCrossRefGoogle Scholar
  19. Keeley EC, Boura JA, Grines CL (2003) Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 361:13–20PubMedCrossRefGoogle Scholar
  20. Kloner RA, Rezkalla SH (2004) Cardiac protection during acute myocardial infarction: where do we stand in 2004? J Am Coll Cardiol 44:276–286PubMedCrossRefGoogle Scholar
  21. Litt MR, Jeremy RW, Weisman HF, Winkelstein JA, Becker LC (1989) Neutrophil depletion limited to reperfusion reduces myocardial infarct size after 90 minutes of ischemia. Evidence for neutrophil-mediated reperfusion injury. Circulation 80:1816–1827PubMedCrossRefGoogle Scholar
  22. Lu L, Chen SS, Zhang JQ, Ramires FJ, Sun Y (2004) Activation of nuclear factor-kappaB and its proinflammatory mediator cascade in the infarcted rat heart. Biochem Biophys Res Commun 321:879–885PubMedCrossRefGoogle Scholar
  23. McAteer MA, Sibson NR, von Zur Muhlen C, Schneider JE, Lowe AS, Warrick N, Channon KM, Anthony DC, Choudhury RP (2007) In vivo magnetic resonance imaging of acute brain inflammation using microparticles of iron oxide. Nat Med 13:1253–1258PubMedCrossRefGoogle Scholar
  24. McAteer MA, Schneider JE, Ali ZA, Warrick N, Bursill CA, von zur Muhlen C, Greaves DR, Neubauer S, Channon KM, Choudhury RP (2008) Magnetic resonance imaging of endothelial adhesion molecules in mouse atherosclerosis using dual-targeted microparticles of iron oxide. Arterioscler Thromb Vasc Biol 28:77–83PubMedCrossRefGoogle Scholar
  25. McAteer MA, Akhtar AM, von zur Muhlen C, Choudhury RP (2010) An approach to molecular imaging of atherosclerosis, thrombosis, and vascular inflammation using microparticles of iron oxide. Atherosclerosis 209:18–27PubMedCrossRefGoogle Scholar
  26. Montet X, Montet-Abou K, Reynolds F, Weissleder R, Josephson L (2006) Nanoparticle imaging of integrins on tumor cells. Neoplasia 8:214–222PubMedCrossRefGoogle Scholar
  27. Nahrendorf M, Jaffer FA, Kelly KA, Sosnovik DE, Aikawa E, Libby P, Weissleder R (2006) Noninvasive vascular cell adhesion molecule-1 imaging identifies inflammatory activation of cells in atherosclerosis. Circulation 114:1504–1511PubMedCrossRefGoogle Scholar
  28. Nahrendorf M, Sosnovik D, Chen JW, Panizzi P, Figueiredo JL, Aikawa E, Libby P, Swirski FK, Weissleder R (2008) Activatable magnetic resonance imaging agent reports myeloperoxidase activity in healing infarcts and noninvasively detects the antiinflammatory effects of atorvastatin on ischemia-reperfusion injury. Circulation 117:1153–1160PubMedCrossRefGoogle Scholar
  29. Sakhalkar HS, Dalal MK, Salem AK, Ansari R, Fu J, Kiani MF, Kurjiaka DT, Hanes J, Shakesheff KM, Goetz DJ (2003) Leukocyte-inspired biodegradable particles that selectively and avidly adhere to inflamed endothelium in vitro and in vivo. Proc Natl Acad Sci USA 100:15895–15900PubMedCrossRefGoogle Scholar
  30. Schwarz M, Meade G, Stoll P, Ylanne J, Bassler N, Chen YC, Hagemeyer CE, Ahrens I, Moran N, Kenny D, Fitzgerald D, Bode C, Peter K (2006) Conformation-specific blockade of the integrin GPIIb/IIIa: a novel antiplatelet strategy that selectively targets activated platelets. Circ Res 99:25–33PubMedCrossRefGoogle Scholar
  31. Sosnovik DE, Garanger E, Aikawa E, Nahrendorf M, Figuiredo JL, Dai G, Reynolds F, Rosenzweig A, Weissleder R, Josephson L (2009a) Molecular MRI of cardiomyocyte apoptosis with simultaneous delayed-enhancement MRI distinguishes apoptotic and necrotic myocytes in vivo: potential for midmyocardial salvage in acute ischemia. Circ Cardiovasc Imaging 2:460–467PubMedCrossRefGoogle Scholar
  32. Sosnovik DE, Nahrendorf M, Panizzi P, Matsui T, Aikawa E, Dai G, Li L, Reynolds F, Dorn GW 2nd, Weissleder R, Josephson L, Rosenzweig A (2009b) Molecular MRI detects low levels of cardiomyocyte apoptosis in a transgenic model of chronic heart failure. Circ Cardiovasc Imaging 2:468–475PubMedCrossRefGoogle Scholar
  33. von zur Muhlen C, von Elverfeldt D, Moeller JA, Choudhury RP, Paul D, Hagemeyer CE, Olschewski M, Becker A, Neudorfer I, Bassler N, Schwarz M, Bode C, Peter K (2008) Magnetic resonance imaging contrast agent targeted toward activated platelets allows in vivo detection of thrombosis and monitoring of thrombolysis. Circulation 118:258–267PubMedCrossRefGoogle Scholar
  34. von zur Muhlen C, Peter K, Ali ZA, Schneider JE, McAteer MA, Neubauer S, Channon KM, Bode C, Choudhury RP (2009) Visualization of activated platelets by targeted magnetic resonance imaging utilizing conformation-specific antibodies against glycoprotein IIb/IIIa. J Vasc Res 46:6–14PubMedCrossRefGoogle Scholar
  35. von Zur MuhlenC, von Elverfeldt D, Choudhury RP, Ender J, Ahrens I, Schwarz M, Hennig J, Bode C, Peter K (2008) Functionalized magnetic resonance contrast agent selectively binds to glycoprotein IIb/IIIa on activated human platelets under flow conditions and is detectable at clinically relevant field strengths. Mol Imaging 7:59–67Google Scholar
  36. Wang QD, Pernow J, Sjoquist PO, Ryden L (2002) Pharmacological possibilities for protection against myocardial reperfusion injury. Cardiovasc Res 55:25–37PubMedCrossRefGoogle Scholar
  37. Winter PM, Morawski AM, Caruthers SD, Fuhrhop RW, Zhang H, Williams TA, Allen JS, Lacy EK, Robertson JD, Lanza GM, Wickline SA (2003) Molecular imaging of angiogenesis in early-stage atherosclerosis with alpha(v)beta3-integrin-targeted nanoparticles. Circulation 108:2270–2274PubMedCrossRefGoogle Scholar
  38. Zhao ZQ, Lefer DJ, Sato H, Hart KK, Jefforda PR, Vinten-Johansen J (1997) Monoclonal antibody to ICAM-1 preserves postischemic blood flow and reduces infarct size after ischemia-reperfusion in rabbit. J Leukoc Biol 62:292–300PubMedGoogle Scholar
  39. Zhu D, White RD, Hardy PA, Weerapreeyakul N, Sutthanut K, Jay M (2006) Biocompatible nanotemplate-engineered nanoparticles containing gadolinium: stability and relaxivity of a potential MRI contrast agent. J Nanosci Nanotechnol 6:996–1003PubMedCrossRefGoogle Scholar

Copyright information

© European Biophysical Societies' Association 2012

Authors and Affiliations

  • Stuart M. Grieve
    • 1
    • 2
  • Jacob Lønborg
    • 1
    • 3
  • Jawad Mazhar
    • 1
    • 4
  • Timothy C. Tan
    • 1
    • 5
  • Edwin Ho
    • 1
  • Chia-Chi Liu
    • 1
  • William Lay
    • 1
  • Anthony J. Gill
    • 6
  • Philip Kuchel
    • 7
  • Ravinay Bhindi
    • 1
    • 4
  • Gemma A. Figtree
    • 1
    • 4
  1. 1.North Shore Heart Research Group, Kolling InstituteUniversity of SydneySydneyAustralia
  2. 2.Department of RadiologyRoyal Prince Alfred HospitalSydneyAustralia
  3. 3.Department of Cardiology, RigshospitaletCopenhagen University HospitalCopenhagenDenmark
  4. 4.Department of CardiologyRoyal North Shore HospitalSydneyAustralia
  5. 5.Department of CardiologyWestmead HospitalSydneyAustralia
  6. 6.Department of Anatomical PathologyRoyal North Shore HospitalSydneyAustralia
  7. 7.School of Molecular BioscienceUniversity of SydneySydneyAustralia

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